TY - JOUR
T1 - Intermittent fasting preserves beta-cell mass in obesity-induced diabetes via the autophagy-lysosome pathway
AU - Liu, Haiyan
AU - Javaheri, Ali
AU - Godar, Rebecca J.
AU - Murphy, John
AU - Ma, Xiucui
AU - Rohatgi, Nidhi
AU - Mahadevan, Jana
AU - Hyrc, Krzysztof
AU - Saftig, Paul
AU - Marshall, Connie
AU - McDaniel, Michael L.
AU - Remedi, Maria S.
AU - Razani, Babak
AU - Urano, Fumihiko
AU - Diwan, Abhinav
N1 - Funding Information:
This study was supported by grants from National Institutes of Health (HL107594; and DRC, Grant No. P30 DK020579) and Department of Veterans Affairs (I01BX000448, 1I01BX001969) to A.D, from the NIH (R01 DK098584) to MSR; and the Deutsche Forschungsgemeinschaft to P.S. AJ was supported by K08HL138262-01 and 5-T32-HL07081–40 from the NHLBI. We also acknowledge support from the NIH Shared Instrumentation Grant (S10 RR027552) for support through the Hope Center Neuroim-aging Core; and support from the Electron Microscopy Core and Advanced Imaging and Tissue Analysis Core of the Digestive Disease Research Core Center (DDRCC) at Washington University School of Medicine.
Funding Information:
This study was supported by grants from National Institutes of Health (HL107594; and DRC, Grant No. P30 DK020579) and Department of Veterans Affairs (I01BX000448, 1I01BX001969) to A.D, from the NIH (R01 DK098584) to MSR; and the Deutsche Forschungsgemeinschaft to P.S. AJ was supported by K08HL138262-01 and 5-T32-HL07081?40 from the NHLBI. We also acknowledge support from the NIH Shared Instrumentation Grant (S10 RR027552) for support through the Hope Center Neuroimaging Core; and support from the Electron Microscopy Core and Advanced Imaging and Tissue Analysis Core of the Digestive Disease Research Core Center (DDRCC) at Washington University School of Medicine. The authors thank Clay F. Semenkovich, Washington University, for helpful scientific discussions.
Publisher Copyright:
© 2017 Taylor & Francis.
PY - 2017/11/2
Y1 - 2017/11/2
N2 - Obesity-induced diabetes is characterized by hyperglycemia, insulin resistance, and progressive beta cell failure. In islets of mice with obesity-induced diabetes, we observe increased beta cell death and impaired autophagic flux. We hypothesized that intermittent fasting, a clinically sustainable therapeutic strategy, stimulates autophagic flux to ameliorate obesity-induced diabetes. Our data show that despite continued high-fat intake, intermittent fasting restores autophagic flux in islets and improves glucose tolerance by enhancing glucose-stimulated insulin secretion, beta cell survival, and nuclear expression of NEUROG3, a marker of pancreatic regeneration. In contrast, intermittent fasting does not rescue beta-cell death or induce NEUROG3 expression in obese mice with lysosomal dysfunction secondary to deficiency of the lysosomal membrane protein, LAMP2 or haplo-insufficiency of BECN1/Beclin 1, a protein critical for autophagosome formation. Moreover, intermittent fasting is sufficient to provoke beta cell death in nonobese lamp2 null mice, attesting to a critical role for lysosome function in beta cell homeostasis under fasting conditions. Beta cells in intermittently-fasted LAMP2- or BECN1-deficient mice exhibit markers of autophagic failure with accumulation of damaged mitochondria and upregulation of oxidative stress. Thus, intermittent fasting preserves organelle quality via the autophagy-lysosome pathway to enhance beta cell survival and stimulates markers of regeneration in obesity-induced diabetes.
AB - Obesity-induced diabetes is characterized by hyperglycemia, insulin resistance, and progressive beta cell failure. In islets of mice with obesity-induced diabetes, we observe increased beta cell death and impaired autophagic flux. We hypothesized that intermittent fasting, a clinically sustainable therapeutic strategy, stimulates autophagic flux to ameliorate obesity-induced diabetes. Our data show that despite continued high-fat intake, intermittent fasting restores autophagic flux in islets and improves glucose tolerance by enhancing glucose-stimulated insulin secretion, beta cell survival, and nuclear expression of NEUROG3, a marker of pancreatic regeneration. In contrast, intermittent fasting does not rescue beta-cell death or induce NEUROG3 expression in obese mice with lysosomal dysfunction secondary to deficiency of the lysosomal membrane protein, LAMP2 or haplo-insufficiency of BECN1/Beclin 1, a protein critical for autophagosome formation. Moreover, intermittent fasting is sufficient to provoke beta cell death in nonobese lamp2 null mice, attesting to a critical role for lysosome function in beta cell homeostasis under fasting conditions. Beta cells in intermittently-fasted LAMP2- or BECN1-deficient mice exhibit markers of autophagic failure with accumulation of damaged mitochondria and upregulation of oxidative stress. Thus, intermittent fasting preserves organelle quality via the autophagy-lysosome pathway to enhance beta cell survival and stimulates markers of regeneration in obesity-induced diabetes.
KW - autophagy
KW - beta cells
KW - diabetes
KW - intermittent fasting
KW - lysosomes
UR - http://www.scopus.com/inward/record.url?scp=85034829751&partnerID=8YFLogxK
U2 - 10.1080/15548627.2017.1368596
DO - 10.1080/15548627.2017.1368596
M3 - Article
C2 - 28853981
AN - SCOPUS:85034829751
SN - 1554-8627
VL - 13
SP - 1952
EP - 1968
JO - Autophagy
JF - Autophagy
IS - 11
ER -